Enhanced prostatic Esr1+ luminal epithelial cells in the absence of SRD5A2.

Steroid 5α reductase 2 (SRD5A2) converts testosterone to dihydrotestosterone and is crucial for prostatic development. 5α reductase inhibitors (5ARI) reduce prostate size in benign prostate hyperplasia (BPH) and ameliorate lower urinary tract symptoms secondary to BPH. However, the mechanisms of 5ARI functioning are still not fully understood. Here, we used a Srd5a2-/- mouse model and employed single-cell RNA sequencing to explore the impact of SRD5A2 absence on prostate cellular heterogeneity. Significant alterations in luminal epithelial cell (LE) populations were observed, alongside an increased proportion and proliferative phenotype of estrogen receptor 1 (ESR1)+ LE2 cells, following an SRD5A2-independent ESR1 differentiation trajectory. LE2 cells exhibited enhanced estrogen response gene signatures, suggesting an alternative pathway for prostate growth when SRD5A2 is absent. Human prostate biopsy analysis revealed an inverse correlation between the expressions of SRD5A2 and LE2 markers (ESR1/PKCα), and an inverse correlation between SRD5A2 and the clinical efficiency of 5ARI. These findings provide insights into 5ARI resistance mechanisms and potential alternative therapies for BPH-related lower urinary tract symptoms. © 2024 The Pathological Society of Great Britain and Ireland.

Targeting the Metabolic Enzyme PGAM2 Overcomes Enzalutamide Resistance in Castration-Resistant Prostate Cancer by Inhibiting BCL2 Signaling.

The next-generation androgen receptor (AR) inhibitor enzalutamide is the mainstay treatment for metastatic prostate cancer. Unfortunately, resistance occurs rapidly in most patients, and once resistance occurs, treatment options are limited. Therefore, there is an urgent need to identify effective targets to overcome enzalutamide resistance. Here, using a genome-wide CRISPR-Cas9 library screen, we found that targeting a glycolytic enzyme, phosphoglycerate mutase PGAM2, significantly enhanced the sensitivity of enzalutamide-resistant prostate cancer cells to enzalutamide both in vivo and in vitro. Inhibition of PGAM2 together with enzalutamide treatment triggered apoptosis by decreasing levels of the antiapoptotic protein BCL-xL and increasing activity of the proapoptotic protein BAD. Mechanistically, PGAM2 bound to 14-3-3ζ and promoted its interaction with phosphorylated BAD, resulting in activation of BCL-xL and subsequent resistance to enzalutamide-induced apoptosis. In addition, high PGAM2 expression, which is transcriptionally regulated by AR, was associated with shorter survival and rapid development of enzalutamide resistance in patients with prostate cancer. Together, these findings provide evidence of a nonmetabolic function of PGAM2 in promoting enzalutamide resistance and identify PGAM2 inhibition as a promising therapeutic strategy for enzalutamide-resistant prostate cancer. SIGNIFICANCE: PGAM2 promotes resistance to enzalutamide by activating antiapoptotic BCL-xL and suppressing apoptosis, indicating that PGAM2 is a potential target for overcoming enzalutamide resistance in prostate cancer.

C1q/TNF-related protein 4 mediates proliferation and migration of vascular smooth muscle cells during vascular remodelling.

BACKGROUND: Vascular remodelling is an essential pathophysiological state in many circulatory diseases. Abnormal vascular smooth muscle cell (VSMC) behaviour leads to neointimal formation and may eventually results in major adverse cardiovascular events. The C1q/TNF-related protein (C1QTNF) family is closely associated with cardiovascular disease. Notably, C1QTNF4 has unique two C1q domains. However, the role of C1QTNF4 in vascular diseases remains unclear. METHODS: C1QTNF4 expression was detected in human serum and artery tissues using ELISA and multiplex immunofluorescence (mIF) staining. Scratch assay, transwell assay and confocal microscopy were used to investigate C1QTNF4 effects on VSMC migration. EdU incorporation, MTT assay and cell counting experiment revealed C1QTNF4 effects on VSMC proliferation. C1QTNF4-transgenic, C1QTNF4-/- and AAV9-mediated VSMC-specific C1QTNF4 restoration C1QTNF4-/- mouse and rat disease models were generated. RNA-seq, quantitative real-time PCR, western blot, mIF, proliferation and migration assays were used to investigate the phenotypic characteristics and underlying mechanisms. RESULTS: Serum C1QTNF4 levels were decreased in patients with arterial stenosis. C1QTNF4 shows colocalisation with VSMC in human renal arteries. In vitro, C1QTNF4 inhibits VSMC proliferation and migration and alters VSMC phenotype. In vivo, an adenovirus-infected rat balloon injury model, C1QTNF4-transgenic and C1QTNF4-/- mouse wire-injury models with or without VSMC-specific C1QTNF4 restoration were established to mimic the VSMC repair and remodelling. The results show that C1QTNF4 decreases intimal hyperplasia. Especially, we displayed the rescue effect of C1QTNF4 in vascular remodelling using AAV vectors. Next, transcriptome analysis of artery tissue identified the potential mechanism. In vitro and in vivo experiments confirm that C1QTNF4 ameliorates neointimal formation and maintains vascular morphology by downregulating the FAK/PI3K/AKT pathway. CONCLUSIONS: Our study demonstrated that C1QTNF4 is a novel inhibitor of VSMC proliferation and migration that acts by downregulating the FAK/PI3K/AKT pathway, thus protecting blood vessels from abnormal neointima formation. These results provide new insights into promising potent treatments for vascular stenosis diseases.

Overexpression of Ubiquitin-Conjugating Enzyme E2C Is Associated with Worsened Prognosis in Prostate Cancer.

To evaluate the role of ubiquitin-conjugating enzyme E2C (UBE2C) in prostate cancer (PCa) progression and prognosis, the TCGA and our PCa tissue microarray cohort were included in the study. Weighted gene co-expression network analysis (WGCNA) and non-negative matrix factorization were used to cluster patients and to screen genes that play a vital role in PCa progression (hub gene). Immunohistochemistry staining was used to evaluate the protein level of UBE2C in prostatic tissues. Through WGCNA, we found a gene co-expression module (named the purple module) that is strongly associated with the Gleason score, pathologic T stage, and biochemical recurrent status. Genes in the purple module are enriched in cell cycle and P53 signaling and help us to cluster patients into two groups with distinctive biochemical recurrent survival rates and TP53 mutation statuses. Further analysis showed UBE2C served as a hub gene in the purple module. The expression of UBE2C in PCa was significantly higher than that in paracancerous tissues and was remarkably associated with pathologic grade, Gleason score, and prognosis in PCa patients. To conclude, UBE2C is a PCa-progress-related gene and a biomarker for PCa patients. Therapy targeting UBE2C may serve as a promising treatment of PCa in the future.

Single-cell RNA-sequencing technology demonstrates the heterogeneity between aged prostate peripheral and transitional zone.

BACKGROUND: Identifying cellular and functional heterogeneity within aged prostate is critical for understanding the spatial distribution of prostate diseases. METHODS: Aged human prostate peripheral zone (PZ) and transitional zone (TZ) tissues were used for single-cell RNA-sequencing. Results were validated by immunofluorescence staining. RESULTS: We found that club/hillock epithelial cells, compared with other epithelial cells, had significantly higher NOTCH signaling activity and expressed higher levels of neuro-stems but lower androgen-related genes. These cells were primarily found in the TZ and provided a stem-like niche around the proximal prostate ducts. Significant heterogeneity was observed in the aged luminal population. A novel TFF3+ luminal subtype with elevated MYC and E2F pathway activities was observed, primarily in the PZ. Further analysis revealed that epithelial cells in the TZ had higher levels of stem- and inflammation-related pathway activities but lower androgen/lineage-related pathway activities than those in the PZ. Notably, the activation of MYC, E2F and DNA repair pathways significantly increased in PZ luminal cells. In the immune landscape, we found that the immune microenvironment in the TZ is more complex and disordered with more infiltration of NK and Treg cells. CD8 T cell and macrophage in the TZ exhibit both inflammation activation and suppression phenotypes. In the stroma, the TZ had a higher fibroblast density, and fibroblasts in the TZ exhibited stronger transcriptome activity in immunity and proliferation. Ligand-receptor interaction analysis revealed that fibroblasts could contribute to a NOTCH signaling niche for club/hillock cells in the TZ and balance the prostate immune microenvironment. The activation of stem properties, inflammatory infiltration and loss of androgen/lineage activity are prominent features distinguishing the TZ from PZ. CONCLUSIONS: Our study explains the heterogeneity between the TZ and PZ of aged prostate, which may help understand the spatial distribution of prostate diseases and establish a foundation for novel target discovery.

Single black men have the worst prognosis with localized prostate cancer.

INTRODUCTION: To determine whether marital status combined with race serve as prognostic factors for survival in localized prostate cancer. MATERIALS AND METHODS: Patients with localized prostate cancer were retrospectively extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Chi-square test was used to investigate the association between marital status combined with race and other variables. Gray's test was used to compare the cumulative incidence function of different variables. Multivariable analysis was conducted to assess prognostic factors after adjusting for other variables. RESULTS: A total of 207,219 patients with localized prostate cancer from the SEER database from 2010 to 2016 were eligible. We found that black or single patients had the highest risk of mortality (p < 0.001). When marital status and race were combined, single black patients had the worst prognosis after adjusting for other variables (hazard ratio = 1.93, 95% confidence interval: 1.58-2.35; p < 0.001). Married status had a prognostic advantage in all races. In the same marital groups, whites and Asians had lower risk of prostate cancer-specific mortality and other-cause mortality than blacks with married and single status (p < 0.001). CONCLUSIONS: Marital status and race serve as prognostic factors for localized prostate cancer. Blacks or single individuals had higher risk of mortality when considered independently, and single black patients had the worst prognosis. Furthermore, married status was an advantage in the same race group, and whites and Asians had lower risk than blacks with married and single status. Accordingly, the interaction between race and marital status on prostate cancer prognosis in clinical practice should be assessed carefully.

Zonal Growth Pattern of the Prostate Is Affected by Age and Body Mass Index.

PURPOSE: As men age, the prostate continues to grow on average 2.5% per year. While the variable growth rate of the total prostate gland is recognized, the growth rate of different prostate zones remains largely unclear. We evaluated the growth patterns of the prostate zones and identified clinical parameters contributing to the zonal growth rates. MATERIALS AND METHODS: Prostate magnetic resonance imaging (MRI) data and clinical information were obtained retrospectively on 156 patients who had at least 3 prostate MRIs between 2003 and 2018. Different prostate zonal volumes were measured and analyzed. The outcome was analyzed using linear regression. RESULTS: We observed that prostate growth rates vary depending on body mass index (BMI), transition zone index (TZI), the prostate zone and 5-alpha reductase inhibitor (5ARI) use. The peripheral zone volume growth rates increased with age and peaked at 60-70 years of age (p=0.047), while the transition zone volume demonstrates continuous growth without a peak through all ages. BMI and TZI are associated with the growth rate of the peripheral zone (p=0.026, p <0.001, respectively) but not the transition zone growth rate. 5ARI use is significantly associated with the reduction in the transition zone growth rate (p=0.033), not the peripheral zone. In addition, patients with TZI greater than 60% had the most significant reduction in the transition zone growth rate while taking 5ARI (p <0.001). CONCLUSIONS: Transition and peripheral zones of the prostate grow at variable rates. BMI and TZI affect peripheral zone growth rate, while 5ARI use reduces the transition zone growth rate.

Comparison of the Effect and Complications of Sequential Bilateral Arthroplasty at Different Time Intervals and Simultaneous Bilateral Total Knee Arthroplasty: A Single-Centre Retrospective Cohort Study.

INTRODUCTION: To the authors' knowledge, there is no current consensus regarding the optimal interprocedural interval for patients who have undergone bilateral total knee arthroplasty (BTKA). The purpose of this study is to evaluate complication rates and functional outcome in patients who have undergone BTKA (simultaneous or sequential at different time intervals), and to determine an optimal time frame for the second knee. METHODS: Data from 315 patients who were able to tolerate simultaneous BTKA according to the anaesthesiologist's preoperative assessment between 2016 and 2020 were analysed retrospectively. According to the operative time interval, they were divided into simultaneous, ≤ 1-month sequential, 1- to 3-month sequential, and ≥ 3-month sequential BTKA groups. The primary outcomes were revision and readmission rates during the follow-up period, and the secondary outcomes were hospital length of stay (LOS), transfusion and postoperative complications. RESULTS: There was no difference in the implant survival or readmission rate between the groups (p > 0.05). Multivariable linear regression showed that interprocedural interval and body mass index (BMI) affected LOS; the LOS of simultaneous BTKA was the shortest (p < 0.05). BMI was associated with an increased LOS of 0.25 days (95% CI 0.02-0.48, p = 0.03). A modified Poisson regression model showed that the odds of blood transfusion were reduced in sequential BTKAs of any interval (p < 0.05), and preoperative haemoglobin (Hb) was also a risk factor (RR 0.96, 95% CI 0.95-0.98, p < 0.001). The interprocedural interval was not a risk factor for postoperative cardiovascular and cerebrovascular complications. CONCLUSION: For appropriate patients, simultaneous BTKA is beneficial. However, higher preoperative haemoglobin was required to mitigate the high blood transfusion rate associated with simultaneous surgeries. If suitable patients refuse simultaneous BTKA for other non-medical reasons, sequential BTKA with an interval greater than 1 month is recommended.

Developing a nomogram for predicting intravesical recurrence after radical nephroureterectomy: a retrospective cohort study of mainland Chinese patients.

OBJECTIVE: To evaluate the role of Ki-67 in predicting subsequent intravesical recurrence following radical nephroureterectomy and to develop a predictive nomogram for upper tract urothelial carcinoma patients. METHODS: This retrospective analysis involved 489 upper tract urothelial carcinoma patients who underwent radical nephroureterectomy with bladder cuff excision. The data set was randomly split into a training cohort of 293 patients and a validation cohort of 196 patients. Immunohistochemical analysis was used to assess the immunoreactivity of the biomarker Ki-67 in the tumor tissues. A multivariable Cox regression model was utilized to identify independent intravesical recurrence predictors after radical nephroureterectomy before constructing a nomographic model. Predictive accuracy was quantified using time-dependent receiver operating characteristic curve. Decision curve analysis was performed to evaluate the clinical benefit of models. RESULTS: With a median follow-up of 54 months, intravesical recurrence developed in 28.2% of this sample (n = 137). Tumor location, multifocality, pathological T stage, surgical approach, bladder cancer history and Ki-67 expression levels were independently associated with intravesical recurrence (all P < 0.05). The full model, which intercalated Ki-67 with traditional clinicopathological parameters, outperformed both the basic model and Xylinas' model in terms of discriminative capacity (all P < 0.05). Decision-making analysis suggests that the more comprehensive model can also improve patients' net benefit. CONCLUSIONS: This new model, which intercalates the Ki-67 biomarker with traditional clinicopathological factors, appears to be more sensitive than nomograms previously tested across mainland Chinese populations. The findings suggest that Ki-67 could be useful for determining risk-stratified surveillance protocols following radical nephroureterectomy and in generating an individualized strategy based around intravesical recurrence predictions.

Prognostic autophagy model based on CASP4 and BIRC5 expression in patients with renal cancer: independent datasets-based study.

The purpose of this study was to identify key autophagy-related genes (ARGs) in patients with renal cancer (RC) by bioinformatics analysis, and to clarify their potential prognostic value. Thirty-eight differentially expressed ARGs were identified between RC and normal tissues based on The Cancer Genome Atlas database. Functional enrichment analysis suggested that autophagy may play a tumor-promoting role in the initiation of RC. We established a prognostic model with two ARGs (CASP4 and BIRC5) demonstrating significant correlations in expression levels with patient overall survival (OS). Multivariate Cox regression analysis showed that age and the autophagy genes prognostic model were independent prognostic factors for patients with RC. Considering the known prognostic significance of clinical stage in RC, we constructed a nomogram based on age, clinical stage, and the prognostic model. The prognostic model was verified in a separate validation set and external cohort of patients from Beijing Hospital. Patients of low and high risk were defined based on the median risk value calculated by the model and the high risk appeared associated with a significant shorter OS (P < 0.01). Overall, our findings reveal that ARGs have potential prognostic value in patients with RC, providing new directions for targeted therapy.

Oncological impact of different distal ureter managements during radical nephroureterectomy for primary upper urinary tract urothelial carcinoma.

BACKGROUND: The current standard surgical treatment for non-metastatic upper urinary tract urothelial carcinoma (UTUC) is radical nephroureterectomy (RNU) with bladder cuff excision (BCE). Typically, BCE techniques are classified in one of the following three categories: An open technique described as intrasvesical incision of the bladder cuff, a transurethral incision of the bladder cuff (TUBC), and an extravesical incision of the bladder cuff (EVBC) method. Even though each of these management techniques are widely used, there is no consensus about which surgical intervention is superior, with the best oncologic outcomes. AIM: To investigate the oncological outcomes of three BCE methods during RNU for primary UTUC patients. METHODS: We retrospectively analyzed the data of 248 primary UTUC patients, who underwent RNU with BCE between January 2004 to December 2018. Patients were analyzed according to each BCE method. Data extracted included patient demographics, perioperative parameters, and oncological outcomes. Statistical analyses were performed using chi-square and log-rank tests. The Cox proportional hazards regression model was utilized to identify independent predictors. P < 0.05 was considered statistically significant. RESULTS: Of the 248 participants, 39.9% (n = 99) underwent intrasvesical incision of the bladder cuff, 38.7% (n = 96) EVBC, and 21.4% (n = 53) TUBC. At a median follow-up of 44.2 mo, bladder recurrence developed in 17.2%, 12.5%, and 13.2% of the cases, respectively. Cancer-specific deaths occurred in 11.1%, 5.2%, and 7.5% of patients, respectively. Kaplan-Meier survival curves with a log-rank test highlighted no significant differences in intravesical recurrence-free survival, cancer-specific survival, and overall survival among these approaches with P values of 0.987, 0.825, and 0.497, respectively. Multivariate analysis showed that the lower ureter location appears to have inferior intravesical recurrence-free survival (P = 0.042). However, cancer-specific survival and overall survival were independently influenced by tumor stage (hazard ratio [HR] = 8.439; 95% confidence interval: 2.424-29.377; P = 0.001) and lymph node status (HR = 14.343; 95%CI: 5.176-39.745; P < 0.001). CONCLUSION: All three techniques had comparable outcomes; although, EVBC and TUBC are minimally invasive. While based upon rather limited data, these findings will support urologists in blending experience with evidence to inform patient choices. However, larger, rigorously designed, multicenter studies with long term outcomes are still required.

Identification and validation of an immune-related gene-based prognostic index for bladder cancer.

Bladder cancer (BLCA) is a common malignancy arising from the urinary bladder and therapeutic options are limited. However, the mechanisms underlying BLCA development are poorly understood. In this study, robust rank aggregation was used to integrate five GEO BLCA microarray datasets for identifying differentially expressed genes (DEGs) between non-muscular invasive BLCA and muscular invasive BLCA. One-hundred fifty-four DEGs related to the degree of BLCA infiltration, including 24 immune-related genes (IRGs), were identified. Missense mutations were the most common type in IRGs. Ten hub IRGs were identified by protein-protein interaction network analysis. Gene set enrichment analysis and gene set variation analysis of two novel BLCA-related genes (TYROBP and FCER1G) revealed that they were related to immunity. Nine survival-related IRGs were identified, and their potential regulation by transcription factors was analyzed. An immune-related gene-based prognostic index (IRGPI) comprising CTSE, CXCL10, FAM3B, MMP9, OLR1, and S100P was constructed using multivariate analysis. The reliability of the IRGPI was evaluated using independent datasets, and correlations between the IRGPI and clinicopathological characteristics, as well as the immune microenvironment, were evaluated. Finally, a nomogram was established to evaluate the prognosis of patients with BLCA. Our data provide new insights into the pathogenesis of BLCA and target genes for immunotherapy. The application of molecular markers for hierarchical prediction paves the way for precision medicine.

Icaritin reduces prostate cancer progression via inhibiting high-fat diet-induced serum adipokine in TRAMP mice model.

Objective: Obesity resulting from high-fat diets has a close relationship with the morbidity and mortality associated with Prostate cancer (PCa) in males. The anti-cancer role of Icaritin (ICT, a traditional Chinese herbal medicine) has been reported in several types of cancer including PCa. Adipokines are novel adipocyte-specific secretory protein, which plays a key role in the development of various diseases including obesity, diabetes, atherosclerosis, and cancer. However, the function of ICT and the molecular mechanisms underlying its role in PCa regression through modulation of adipokines have not been studied. Here, we assessed the anti-cancer properties of ICT under the influence of human epidermal growth factor receptor type 2 (HER2) pathway modulating adipokines in obese PCa models. Materials and Methods: In this study, we used transgenic adenocarcinoma of mouse prostate (TRAMP), a well-established animal model for the study of PCa pathogenesis. All the animals were fed on a high-fat diet (HFD with 40% fat) and divided into two groups, one received ICT solution of 30 mg/kg body bwt (i.p) while the other group served as control without any ICT treatment. The mortality rate, tumor formation and fat ratio were assessed by histopathological and magnetic resonance analysis at different time points of 20th, 24th and 28th weeks. The protein expression of HER2 and serum levels of adipokines were measured using western blotting, IHC and multiplex immunoassays. The PCa grade in 12 TRAMP mice were longitudinally evaluated to visualize PCa development and progression upon post-surgery using PET/CT scanning. Results: We observed that ICT treatment significantly reduces the total mortality rate of TRAMP mice (p = 0.045) and the percentage of prostate intraepithelial neoplasia (PIN) or PCa (p = 0.029). Interestingly, significantly decreased levels of leptin (p = 0.006 @20th wk) and the elevated levels of adiponectin (p = 0.030 @20th wk) were observed in different subgroups upon ICT treatment in a time-dependent manner. In addition, a decrease level of HER2 (p = 0.032 @28th wk) and an elevated level of PEA3 (p = 0.014 @28th wk) were also detected in ICT treated group. The PET/CT-based imaging showed that ICT vs non-ICT treated mice had different standard uptake value and metastasis. Discussion and Conclusion: Our results showed potent anti-cancer properties of ICT through the modulation of adipokine secretion may alter the expression and activation of HER2 pathway as an alternative mechanism to prevent PCa progression. Altogether, our findings indicate that ICT could be a promising cancer preventive agent with the potential to target and eradicate tumor cells in obese PCa patients.

Immune signature driven by ADT-induced immune microenvironment remodeling in prostate cancer is correlated with recurrence-free survival and immune infiltration.

Androgen deprivation therapy (ADT) is a cornerstone treatment for locally advanced or metastatic prostate cancer (PCa). However, its potential effects on the tumor immune microenvironment (TIM) of PCa patients and the underlying mechanism remain largely unclear. To explore the effects of ADT on PCa TIM, RNA sequencing was performed on six paired pre-ADT biopsy and post-ADT PCa lesions, and five paired paracancerous benign tissues from patients receiving neoadjuvant ADT with locally advanced PCa. Bioinformatics methods including ESTIMATE and ssGSEA were used to evaluate the stromal immune score and immune cell infiltration in PCa and paracancerous tissues. Weighted correlation network analysis was used to screen hub genes in the ADT-induced immune remodeling process. The results showed differences exist between PCa and paracancerous tissues in response to ADT. Compared with paracancerous tissues, the immune remodeling effect of ADT in PCa was more intense. ZFP36, JUNB, and SOCS3 served as hub genes in the ADT-induced immune remodeling process and were associated with PSA recurrent-free survival in the TCGA and our neoadjuvant ADT cohort. To investigate the joint action of the above three hub genes, an immune signature score was constructed. The results showed that immune signature score-based immune subtypes reveal the heterogeneity of the immune microenvironment of PCa and showed significant differences in patient prognosis, tumor immune infiltration, mutation burden, and landscape.

Biomarkers in previous histologically negative prostate biopsies can be helpful in repeat biopsy decision-making processes.

To evaluate whether the addition of biomarkers to traditional clinicopathological parameters may help to increase the accurate prediction of prostate re-biopsy outcome. A training cohort with 98 patients and a validation cohort with 72 patients were retrospectively recruited into our study. Immunohistochemical analysis was used to evaluate the immunoreactivity of a group of biomarkers in the initial negative biopsy normal-looking tissues of the training and validation cohorts. p-STAT3, Mcm2, and/or MSR1 were selected out of 10 biomarkers to construct a biomarker index for predicting cancer and high-grade prostate cancer (HGPCa) in the training cohort based on the stepwise logistic regression analysis; these biomarkers were then validated in the validation cohort. In the training cohort study, we found that the biomarker index was independently associated with the re-biopsy outcomes of cancer and HGPCa. Moreover supplementing the biomarker index with traditional clinical-pathological parameters can improve the area under the receiver operating characteristic curve of the model from 0.722 to 0.842 and from 0.735 to 0.842, respectively, for predicting cancer and HGPCa at re-biopsy. In the decision-making analysis, we found the model supplemented with the biomarker index can improve patients' net benefit. The application of the model to clinical practice, at a 10% risk threshold, would reduce the number of biopsies by 34.7% while delaying the diagnosis of 7.8% cancers and would reduce the number of biopsies by 73.5% while delaying the diagnosis of 17.8% HGPCas. Taken together, supplementing the biomarker index with clinicopathological parameters may help urologists in re-biopsy decision-making processes.

DNA methylation-based classification and identification of bladder cancer prognosis-associated subgroups.

BACKGROUND: Bladder cancer (BCA) is the most common urinary tumor, but its pathogenesis is unclear, and the associated treatment strategy has rarely been updated. In recent years, a deeper understanding of tumor epigenetics has been gained, providing new opportunities for cancer detection and treatment. METHODS: We identified prognostic methylation sites based on DNA methylation profiles of BCA in the TCGA database and constructed a specific prognostic subgroup. RESULTS: Based on the consistent clustering of 402 CpGs, we identified seven subgroups that had a significant association with survival. The difference in DNA methylation levels was related to T stage, N stage, M stage, grade, sex, age, stage and prognosis. Finally, the prediction model was constructed using a Cox regression model and verified using the test dataset; the prognosis was consistent with that of the training set. CONCLUSIONS: The classification based on DNA methylation is closely related to the clinicopathological characteristics of BCA and determines the prognostic value of each epigenetic subtype. Therefore, our findings provide a basis for the development of DNA methylation subtype-specific therapeutic strategies for human bladder cancer.

Methylation of SRD5A2 promoter predicts a better outcome for castration-resistant prostate cancer patients undergoing androgen deprivation therapy.

PURPOSE: To determine whether SRD5A2 promoter methylation is associated with cancer progression during androgen deprivation therapy (ADT) in CRPC. PATIENTS AND METHODS: In a Local CRPC cohort, 42 prostatic specimens were collected from patients who were diagnosed as CRPC and underwent transurethral resection of the prostate (TURP) at Massachusetts General Hospital (MGH). In a metastatic CRPC (Met CRPC) cohort, 12 metastatic biopsies were collected from CRPC patients who would be treated with abiraterone plus dutasteride (Clinical Trial NCT01393730). As controls, 36 benign prostatic specimens were collected from patients undergoing prostate reduction surgery for symptoms of bladder outlet obstruction secondary to benign prostatic hyperplasia (BPH). The methylation status of cytosine-phosphate-guanine (CpG) site(s) at SRD5A2 promoter regions was tested. RESULTS: Compared with benign prostatic tissue, CRPC samples demonstrated higher SRD5A2 methylation in the whole promoter region (Local CRPC cohort: P < 0.001; Met CRPC cohort: P <0.05). In Local CRPC cohort, a higher ratio of methylation was correlated with better OS (R2 = 0.33, P = 0.013). Hypermethylation of specific regions (nucleotides -434 to -4 [CpG# -39 to CpG# -2]) was associated with a better OS (11.3±5.8 vs 6.4±4.4 years, P = 0.001) and PFS (8.4±5.4 vs 4.5±3.9 years, P = 0.003) with cutoff value of 37.9%. Multivariate analysis showed that SRD5A2 methylation was associated with OS independently (whole promoter region: P = 0.035; specific region: P = 0.02). CONCLUSION: Our study demonstrate that SRD5A2 methylation in promoter regions, specifically at CpG# -39 to -2, is significantly associated with better survival for CRPC patients treated with ADT. Recognition of epigenetic modifications of SRD5A2 may affect the choices and sequence of available therapies for management of CRPC.

Caspase 4 Overexpression as a Prognostic Marker in Clear Cell Renal Cell Carcinoma: A Study Based on the Cancer Genome Atlas Data Mining.

The dysregulation of caspase 4 (CASP4) expression is related to the occurrence, development, and outcome of many malignant tumors; however, its role in clear cell renal cell carcinoma (ccRCC) remains unclear. Herein, we investigated the expression of CASP4 in tumor tissues and its relationship with clinical prognosis, immune infiltration, and drug sensitivity status of ccRCC patients. Oncomine and The Cancer Genome Atlas (TCGA) databases were used to determine CASP4 mRNA expression in ccRCC patients. The correlation between CASP4 expression and disease prognosis was evaluated using Kaplan-Meier analysis. Related pathways were obtained from TCGA database via gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA). Meanwhile, genes co-expressing with CASP4 in ccRCC were investigated. Finally, we analyzed the proportion of tumor-infiltrating immune cells (TICs) using the CIBERSORT computational method and assessed CASP4 methylation and its relationship with drug sensitivity. Immunohistochemical analysis of 30 paired ccRCC and adjacent normal tissues confirmed the in silico results. CASP4 mRNA expression in ccRCC was significantly higher than that in the normal tissues, positively correlated with clinicopathological features (clinical stage and pathological grade), and negatively correlated with patient overall survival (OS). GSEA and GSVA showed that the genes in the CASP4-high expression group were primarily enriched in immune-related activities. Moreover, CIBERSORT analysis of TIC proportions revealed that activated CD4 memory T cells were positively correlated with CASP4 expression. Notably, methylation analysis revealed that the abnormal upregulation of CASP4 might be caused by hypomethylation. Finally, we found that the abnormal expression of CASP4 may be related to tumor drug resistance. Overall, our study shows that CASP4 is overexpressed in ccRCC and is an important factor affecting disease prognosis. Hence, CASP4 may serve as a potential prognostic biomarker and therapeutic target in ccRCC.

Cancer-associated fibroblasts promote cisplatin resistance in bladder cancer cells by increasing IGF-1/ERß/Bcl-2 signalling.

While cancer-associated fibroblasts (CAFs) in the tumour microenvironment may play important roles in bladder cancer (BCa) progression, their impacts on BCa chemoresistance remain unclear. Using human BCa samples, we found that tumour tissues possessed more CAFs than did adjacent normal tissues. Both the presence of CAFs in the BCa stroma and the expression of ERß in BCa contribute to chemoresistance, and CAFs and BCa cells interact to affect ERß expression. In vitro co-culture assays demonstrated that compared with normal bladder cells, BCa cells had a higher capacity to induce the transformation of normal fibroblasts into CAFs. When BCa cells were co-cultured with CAFs, their viability, clone formation ability and chemoresistance were increased, whereas their apoptotic rates were downregulated. Dissection of the mechanism revealed that the recruited CAFs increased IGF-1/ERß signalling in BCa cells, which then led to the promotion of the expression of the anti-apoptotic gene Bcl-2. Blocking IGF-1/ERß/Bcl-2 signalling by either an shRNA targeting ERß or an anti-IGF-1 neutralizing antibody partially reversed the capacity of CAFs to increase BCa chemoresistance. The in vivo data also confirmed that CAFs could increase BCa cell resistance to cisplatin by increasing ERß/Bcl-2 signalling. The above results showed the important roles of CAFs within the bladder tumour microenvironment, which could enhance BCa chemoresistance.

Evolving use of social media among Chinese urologists: Opportunity or challenge?

BACKGROUND: Social media has revolutionized the way people communicate, and it has been widely incorporated into medical practice. However, limited data are available regarding the use of social media by Chinese urologists in their practice. METHODS: From 2014 to 2016, during the China Urological Association's (CUA) Annual National Minimally Invasive Urology Academic Conference, an anonymous survey on social media usage was distributed to participant urologists. RESULTS: The results of the survey, which was completed by 665 participants, indicate a conspicuous increase in social media use during the last three years. Regression analysis showed that year (2014 compared to 2016 and 2015), institute location (in the eastern region of China) and age (<35 y) were independent predictors of social media use. Rather than for personal use, an increasing number of respondents said they used social media for professional purposes, and for most respondents, social media has had a positive impact on their practice. However, when posting information on social media, few respondents were aware of the issue of protecting patients' privacy. CONCLUSIONS: Our study demonstrates a dramatic increase in social media use among Chinese urologists, which provides great opportunities for online academic communication and medical education. However, unprofessional use of social media in the medical practice may bring about potential risks and challenges for the further development of social media in medical practice.